Storage of Ampoules Containing Pharmaceutical Formulations Using a Sealed Container Comprising an Oxygen Scavenger

ABSTRACT

Ampoules made of plastics material and containing 0.5 to 5 ml of a pharmaceutical formulation are sealed, together with an oxygen scavenger, within a pouch.

FIELD OF THE INVENTION

The present invention relates to the sealing of containers which can beused for storage of ampoules containing pharmaceutical formulations, andin particular to sealing ampoules within a pouch to reduce or preventoxidation of the formulations over time. The invention relates also tothe sealed containers, in particular containing such ampoules.

BACKGROUND TO THE INVENTION

Pharmaceutical formulations are presented in a variety of differentpackaging, including packaging made of glass, metal, plastic and naturalmaterials. For liquid formulations, e.g. solutions or suspensions, thepackaging must be and remain sealed to prevent leakage. However, anumber of technical and practical difficulties exist with all suchcontainers.

It is known to administer drugs to the lungs of a patient using anebuliser, allowing a patient to administer the drug whilst breathingnormally. The drugs are provided in a unit dose ampoule (UDA),containing a relatively small volume, typically 1 mL-5 mL, of solutionand typically made of plastics material. A method of making ampoules isby Blow-Fill-Seal (BFS), under aseptic conditions, in which the ampouleis formed by extrusion and filled with solution in a multi-part butessentially one-step process. If necessary, and provided the contentsare not heat labile, heat sterilization can be used, e.g. ampoules canbe sterilised by terminal sterilisation methods, i.e. after the ampoulehas been filled and sealed. These methods are well established andaccepted by regulatory authorities worldwide.

A known problem with existing ampoules is that they allow oxygen, othergases and other volatile compounds into the ampoule and allow water(moisture) to exit. Testing of the contents has revealed that, duringstorage, contaminants can pass through the plastic of ampoule walls andbe absorbed into the formulation. As one specific example, unacceptableamounts of vanillin have been found inside ampoules, leading to failureof the product and refusal of regulatory authorities to licence theampoules without safeguards against this external contamination.

The US FDA has recently required that ampoules be over-wrapped by asealing pouch to avoid environmental contamination of the ampoulecontents. The pouch material is typically a tri-laminate of paper and/orpolymer, aluminium and low density polyethylene (LDP). This pouch isregarded as an acceptable solution but the contents are stillsusceptible to oxidation over time. This is particularly an issue withdrug formulations containing oxygen sensitive materials.

It is known to carry out the blow-fill-seal method of making and fillingampoules using nitrogen rather than sterile air during as many steps aspossible in the process. Nitrogen can be used to cap the solution in theampoule. Nitrogen can be introduced into the pouch at the time theampoules are sealed inside the pouch. It is, however, a problem thatusing nitrogen in this process requires specialised equipment ormodification of existing equipment. Health and safety precautionsassociated with the use of nitrogen tend to increase production costsand times and the efficiency of nitrogen entrapment within the pouchvaries and is not totally efficient

An object of the present invention is to solve or at least amelioratethe above-identified issues. An object of preferred embodiments of theinvention is to provide alternative, more preferably improved methods ofstoring ampoules within sealed containers and to provide alternative,preferably improved sealed containers containing ampoules.

SUMMARY OF THE INVENTION

The invention is based on the use of an oxygen scavenger to reduce orprevent oxidation of formulations within ampoules sealed withincontainers.

In a first aspect, the invention provides a sealed container comprising(i) one or more ampoules containing up to 10 ml of a pharmaceuticalformulation and (ii) an oxygen scavenger.

Preferably, the one or more ampoules are made of plastics material. Alsopreferably, the ampoules contain an inhalation pharmaceutical. The oneor more ampoules and the oxygen scavenger are sealed within thecontainer. In some embodiments the container material comprises a metalor metal compound, for example as a coating on or incorporated into anoutside surface.

In a preferred embodiment of the invention the container is a pouch.

In a second aspect, the invention provides a method of reducingoxidative degradation of the content of an ampoule, the methodcomprising sealing the ampoule in a container containing an oxygenscavenger.

In a third aspect, the invention provides a method of reducing moistureegress from a container, the method comprising sealing the container ina pouch containing an oxygen scavenger.

In a fourth aspect, the invention provides a method of sealing anampoule wherein one or more ampoules are sealed within a pouchcontaining an oxygen scavenger.

In a fifth aspect, the invention provides an ampoule made of plasticsmaterial, wherein the ampoule is sealed within a pouch containing anoxygen scavenger.

In a sixth aspect, the invention provides the use of an oxygen scavengerto reduce or prevent oxidation of formulations within one or moreampoules sealed within a container.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides a package made up of an ampoule wrapped within acontainer (e.g. a pouch) comprising an oxygen scavenger. The inventionalso provides 5, 10, 20 30 or more ampoules sealed with the oxygenscavenger within the container, the ampoules conveniently being in astrip. Alternatively, individual ampoules or a combination of one ormore strips and one or more individual ampoules may be sealed within thecontainer. In use the presence of the oxygen scavenger is found tosignificantly reduce the oxygen content within the container, reducingoxidation of the ampoule contents over time and also improving thestability of the ampoule contents.

When a strip of ampoules is sealed within a container and the containeris opened to detach one ampoule from the strip the remaining ampouleswill be exposed to the air. However, this may not be a significantproblem as oxidation of the contents of the ampoules only occurs afterexposure to air over a relatively extended period of time compared totime in storage and the ampoules within the open container wouldtypically all be used before significant oxidation could occur.

In one particular embodiment of the invention the container isre-sealable, allowing a single ampoule to be removed by the user. Thecontainer is then closed to again form a sealed container with theoxygen scavenger still in place. This will act to remove oxygen thatentered the pouch while it was open and to “mop up” any further oxygenthat may diffuse into the pouch. Accordingly, the lower oxygen contentof the container results in reduced oxidation of the contents of theremaining ampoules over time.

In particularly preferred embodiments the container may comprise a pouchwherein the pouch material typically comprises a metal or metal compoundand in some embodiments may comprise a tri-laminate. A typicaltri-laminate composition may comprise paper and/or polymer, aluminiumand low density polyethylene.

In a preferred embodiment of the invention the pouch is gas impermeable.

The ampoules typically comprise or are made of plastics material,especially polypropylene or polyethylene, low or high density or otherpolymer used in manufacture of ampoules or in the drinks industry, e.g.polyethylene terephthalate. Further, the ampoules typically contain apharmaceutical agent, such an inhalation or injection drug, incombination with a pharmaceutically acceptable carrier.

In preferred embodiments of the invention ampoules are made of plasticsmaterial.

The ampoules described herein may typically have a volume of up to 10ml, preferably 0.5 ml or more, or 1 to 5 ml. For example, the ampoulesmay contain 2 to 4 ml of an inhalation pharmaceutical.

In preferred embodiments the ampoules contain 1 ml or more or 2-3 ml ofan inhalation pharmaceutical in a pharmaceutically acceptable carrier.

The oxygen scavenger as used in the invention is generally acommercially available packet or sachet as used and approved by the foodindustry. These oxygen scavengers do not contain leachables therebyavoiding contamination of the product with which they are stored.

The size of oxygen scavenger is typically in the range of 20 to 2000 cc,indicating the volume of oxygen it can absorb, preferably 20 to 1000 cc,more preferably 20 to 500 cc. In one embodiment of the invention a 50 ccpacket is used. Notwithstanding this, it will be apparent to the skilledperson that the size and capacity of the oxygen scavenger used can bevaried depending upon the size of the container, the number of ampouleswithin the container, and the collective volume of the ampoules.

The following examples are provided in support of the invention. Thecontent of the examples are for illustration only and are not intendedto limit the scope of the invention in any way.

Example 1

Packages were prepared each containing one 4-ampoule card and oneFreshPax D-50 oxygen scavenger packet (MultiSorb) and sealed in foil.The packages were prepared in normal atmospheric conditions andcontained air when sealed.

The oxygen scavenging data was analysed at timed intervals using a MoconHead Space Analyzer, the results of which can be seen below:

Time O₂ content within foil 0 hours 19.9% 16 hours 566 ppm 23 hours 435ppm 8 days  0 ppm 14 days  0 ppm 28 days  0 ppm 84 days  0 ppm

A control package with no oxygen scavenger measured 20.5% O₂ at 8 days.

Example 2

This study was designed to demonstrate the effectiveness of oxygenscavengers in preventing degradation of the product, thereby reducingthe impurity levels present in the solution after storage.

The solutions for nebulisation were manufactured in 3 ml LDPE ampoulesusing blow-fill-seal technology. The strips of 5 were then sealed in afoil over wrap to prevent water loss from and external contamination ofthe product.

One batch of Levalbuterol/Ipratropium Bromide Solution for Nebulisation(1.25 mg/0.5 mg/2 ml) combination product was manufactured in 2006. Twosublots of this batch were produced and labelled Sublot 1 (ampoules weresealed in a foil pouch containing an oxygen scavenger) and Sublot 2(ampoules were sealed in a standard foil pouch) stored for 12 months andthen tested as set out below.

The related substance data summarised below is for product that has beenstored for 12 months at 25° C./60% RH.

Batch 04906A Sublot 1 Sublot 2 (No (Oxygen Scavenger) Oxygen Scavenger)Known impurities: H-Tropic acid 0.04% 0.09% Apo-Ipratropium Belowdetectable 0.03% levels Bis Ether Salbutamol 0.15% 0.13% Total knownimpurities 0.19% 0.25% Largest unknown impurity 0.11% 0.19% Totalunknown impurties 0.15% 0.25% Total Impurities 0.34% 0.50%

It can be seen that the impurity levels detected in the product packagedwith the oxygen scavenger were in general 25-40% lower than thoseobserved in product packaged without the oxygen scavenger. Totalimpurity levels showed a 30% reduction when the oxygen scavenger waspresent in the pouch.

This study supports the hypothesis that oxygen scavengers placed withinthe foil pouch improve the stability profile of solutions fornebulisation in ampoules.

Example 3

This study was designed to demonstrate the effectiveness of oxygenscavengers in generating and maintaining an oxygen-free environment whenampoules are stored inside a foil pouch containing an oxygen scavenger.

Ampoules were manufactured using blow-fill-seal technology in normalatmospheric conditions and contained only air when sealed. Packages wereprepared each containing four empty ampoules sealed within an aluminiumpouch containing one FreshPax D-50 oxygen scavenger packet (MultiSorb).

The packages were prepared in normal atmospheric conditions and theoxygen content of air inside the pouches and ampoules on sealing was20.5%. The packages were stored for 18 months and then tested as set outbelow. Oxygen content inside each pouch and inside two ampoules fromeach pouch was measured following internal protocols SAP 392.01 and SEP156.01.

A Systech Gaspace Advance Oxygen Micro Headspace Analyser was used tomeasure oxygen content. The Gaspace instrument was calibrated with acertified gas containing 2.00% of oxygen and was also calibrated withambient air. The oxygen concentration in the headspace of the pouchesand the ampoules was measured using a ‘Timed’ method. A test time of 45seconds was used. A self-adhesive septum was affixed to the pouch andplastic ampoule to ensure a good seal was obtained when sampling.

The oxygen headspace results are presented in the following table:

Oxygen Concentration in Aluminium Oxygen Concentration in PlasticPouches (molar % ± SD) n = 3 Ampoules (molar % ± SD) n = 6 0.00 ± 0.004.99 ± 3.85

It can be seen that oxygen was completely removed from the pouches whilethe ampoules showed a 76% reduction in oxygen content.

In conclusion, the presence of the oxygen scavenger within the pouchesappeared to draw oxygen out of the pouch and out of the headspace of theampoule. Surprisingly, these results contrasted with the findings ofprevious internal studies which have shown that in pouches purged withnitrogen and not containing an oxygen scavenger there was noequilibration of oxygen concentration between the headspace of theampoule and the interior of the pouch (data not shown). One possibleexplanation for the equilibration observed in the present study is thatthe oxygen scavenger acts as a driving force towards equilibrium betweenthe two environments.

Total equilibrium may have been achieved between the ampoules and thepouches in this study following a longer storage period or,alternatively, by using a larger oxygen scavenger. Of course, theampoules used in this study were completely filled with air and thuscontained significantly more oxygen than ampoules filled with activeswould contain. It is possible that due to their lower oxygen volumeampoules filled with actives would reach total equilibrium under theconditions of the present study.

The invention hence provides sealed containers containing ampoules andmethods of obtaining the same.

1. A sealed container comprising a plurality of ampoules containing upto 10 ml of a pharmaceutical formulation and an oxygen scavenger.
 2. Thecontainer of claim 1, wherein the ampoules contain a solution of aninhalation pharmaceutical in a pharmaceutically acceptable carrier. 3.The container of claim 1, wherein the ampoules are made of plasticsmaterial and are manufactured by the blow-fill-seal method. 4.(canceled)
 5. The container of claim 1, containing 10 or more ampoules.6. The container of claim 1, wherein the oxygen scavenger can absorb 20to 2000 cc of oxygen.
 7. The container of claim 1, wherein the containeris made of material comprising a metal or metal compound.
 8. Thecontainer of claim 1, wherein the container is made of materialcomprising aluminum.
 9. The container of claim 1, wherein the containeris re-sealable.
 10. The container of claim 1, wherein the container is apouch.
 11. A method of reducing oxidative degradation of the contents ofa plurality of ampoules containing up to 10 ml of a pharmaceuticalformulation, comprising sealing the ampoules in a container containingan oxygen scavenger.
 12. The method of claim 11, wherein the ampoulescontain a solution of an inhalation pharmaceutical in a pharmaceuticallyacceptable carrier.
 13. The method of claim 11, wherein the ampoules aremade of plastics material manufactured by the blow-fill-seal method. 14.(canceled)
 15. The method of claim 11, wherein the container comprises10 or more ampoules.
 16. The method of claim 11, wherein the oxygenscavenger can absorb 20 to 2000 cc of oxygen.
 17. The method of claim11, wherein the container is made of material comprising a metal ormetal compound.
 18. The method of claim 11, wherein the container ismade of material comprising aluminum.
 19. The method of claim 11,wherein the container is re-sealable.
 20. The method of claim 11,wherein the container is a pouch.
 21. (canceled)
 22. (canceled)
 23. Asealed pouch comprising: (i) 5 or more plastic ampoules containing up to5 ml of an inhalation pharmaceutical in a pharmaceutically acceptablecarrier and (ii) an oxygen scavenger, wherein the pouch is made ofmaterial comprising a metal or a metal compound and the oxygen scavengercan absorb 20 to 2,000 cc of oxygen.